Obesity and drug addiction are diseases that affect a disturbingly large percentage of the population, cost billions of dollars to treat, and represent a increasing drain on our health care system. One factor that contributes to the onset of these diseases is reward seeking behavior. As individuals become obese, they seek and consume food well beyond caloric need. As individuals become addicted, they seek and consume non-nutritive drugs. The mesolimbic system, comprising the ventral tegmental area dopamine neurons and the nucleus accumbens, critically participates in normal reward seeking behavior as well as maladaptive behaviors including the overconsumption of food and drug taking. It has been known for decades that physiological state (hunger, satiety) can modulate reward seeking behavior. However, the mechanisms by which this occurs remain unknown. Here, this gap in knowledge will be addressed by monitoring mesolimbic signaling in real-time during reward seeking behavior towards nutritive (food) and non-nutritive (cocaine, intracranial self-stimulation rewards. The parent grant of this competitive renewal contributed to the establishment of phasic fluctuations in mesolimbic signaling as critical for goal-directed behavior. Indeed, phasic fluctuations in mesolimbic signaling, which occur within hundreds of milliseconds of reward seeking and reward consumption, appear to be especially important for reward-directed behaviors and reinforcement. These fluctuations will be recorded using fast-scan cyclic voltammetry to assay dopamine levels and electrophysiology to assay the firing rates of individual nucleus accumbens neurons. Both techniques allow phasic signals to be correlated with discrete behavioral events in awake, behaving rats. The aims of this proposal are: i) to determine how accumulation of nutrients alters reward-evoked phasic mesolimbic activity during operant responding for food, cocaine or intracranial self-stimulation, and whether metabolism of carbohydrates is necessary for nutrient feedback on phasic mesolimbic signaling and reward seeking; ii) to determine whether central and intra-ventral tegmental area glucagon-like peptide 1 (GLP-1), a centrally active satiety signal, provides negative feedback for phasic mesolimbic signaling and reward seeking; and iii) to determine whether central and intra-ventral tegmental area ghrelin, a centrally active hunger signal, provides positive feedback for phasic mesolimbic signaling and reward seeking. The significance of this work is in the discovery of novel mechanisms underlying normal and maladaptive reward seeking. This will provide therapeutic targets, in both the periphery and within mesolimbic circuitry, for treating disorders of motivatio, including obesity and drug addiction.